COX-2 Inhibitor Controversy

Abstract & Commentary

Synopsis: Current rofecoxib use was associated with a higher risk of acute myocardial infarction or admission for heart failure compared to celecoxib.

Sources: Soloman DH, et al. Circulation. 2004;109: 2068-2073; Mamdani M, et al. Lancet. 2004;363: 1751-1756.

Cyclooxygenase-2 inhibitors are associated with less gastrointestinal bleeding than nonselective non-steroidal anti-inflammatory drugs (NSAIDs), but concern about their cardiovascular effects have arisen. Thus, Solomon and colleagues conducted a case-controlled study of 54,475 patients older than 65 years old identified in a state-sponsored pharmaceutical benefits program for elderly or disabled low-income individuals from 1998-2000. Patients with diseases that may have obscured the relationship between COX-2 drugs and cardiovascular disease were excluded. The case defining event was hospitalization for acute myocardial infarction (AMI), determined by chart review, which was found in 10,895. For each AMI, 4 controls were found and matched for age and sex. Logistic regression analyses were used to assess the relative risk of AMI in patients taking rofecoxib, celecoxib or no NSAIDs. The relative risk of AMI in those on rofecoxib compared to celecoxib was 1.24 (95% CI, 1.05-1.46; P < .02) and compared to no NSAID was 1.14 (1.0-1.3; P = .054). The effect was related to drug dose: rofecoxib 25 mg or less vs celecoxib 200 mg or less (OR, 1.21; 1.01-1.44; P = .036) or rofecoxib > 25 mg vs celcoxib > 200 mg (OR, 1.7; 1.07-2.71; P = .026). Also, risk of AMI with rofecoxib was related to duration of therapy: 1-30 days (OR, 1.4; 1.12-1.75; P = .005) and > 90 days (OR, .96; 0.72-1.25; P = 0.8) compared to celecoxib for a similar duration. Celecoxib was not associated with a higher risk of AMI vs no NSAIDs. Soloman and colleagues concluded that current rofecoxib use was associated with a higher risk of acute myocardial infarction compared to celecoxib or no NSAID use. The risk was treatest during the first 90 days of use, but not thereafter and was higher with doses > 25 mg/d.

Comment by Michael H. Crawford, MD

Although a boon to those with arthritic conditions, concern about adverse cardiac effects based upon the VIGOR study has been a source of continued controversy. In the VIGOR study, rofecoxib 50 mg was compared to naproxen 1000 mg in patients with rheumatoid arthritis. The risk of AMI was elevated in the rofecoxib-treated patients, but aspirin use was prohibited. Other studies have either confirmed or denied this finding, but all had significant limitations. Studies of celecoxib have been generally neutral on AMI risk with a few exceptions. This large observational study certainly puts the onus back on rofecoxib (Merck) to prove that AMI risk is not increased vs celecoxib (Pfizer). Mechanistically, it is not clear why one drug would be more of a problem than the other. Both inhibit COX-2, which decreases the beneficial vasodilatory and platelet effects of prostacyclin, leaving intact the platelet aggregation and vasoconstriction effects of COX-1. Perhaps rofecoxib is just more potent since other studies have shown increased blood pressure on rofecoxib vs celecoxib. The dose relationship would support this as well. Also, the increased risk associated with initial therapy probably has to do with ferreting out the susceptible patients, suggesting that avoiding these drugs in high-risk cardiac patients would make sense.

There are limitations to this study. First, Medicare databases are not always accurate, especially with disease classification. Second, this is a retrospective observational study that could be biased by unrecognized confounders. Third, some patients may have taken their coxib PRN. Finally, the generalizability of a low-income elderly or disabled population may be suspect. However, until a definitive randomized controlled study is completed, it would be advisable to avoid coxibs and especially high doses of rofecoxib in high risk ischemic heart disease patients.

The second study by Mamdani and colleagues is also a retrospective observational study of subjects older than 65 years old in Ontario, Canada, who were divided into 3 cohorts: users of rofecoxib, celecoxib, or non-selective NSAIDs. The case defining event was hospital admission for congestive heart failure. Using a community control group of non-NSAID users proportional hazzard models were constructed accounting for comorbidity. Compared to the controls, rofecoxib and non-selective NSAID users had a higher rate of admissions for heart failure (RR, 1.8; 1.5-2.2; and 1.4; 1.0-1.9, respectively) but not celecoxib (1.0, 0.8-1.3). Among patients with no heart failure admissions for 3 years, only rofecoxib increased the risk of subsequent admission relative to the controls (1.8, 1.4-2.3). Of note, COX-2 users were more likely to have pre-existing cardiovascular disease based upon their history of other drug use. Also, patients without previous use of cardiovascular medications were more likely to be put on them in all the NSAID groups. Soloman et al concluded that there is a higher risk of admission for heart failure among users of rofecxib and non-selective NSAIDs, but not with celecoxib.

Comment by Michael H. Crawford, MD

The Mamdani study is interesting because this same group using the same database were unable to demonstrate a difference in AMI rates between refecoxib and celecoxib, but in that study patients with NSAID use < 30 days were excluded. This is likely the most vulnerable timeframe based upon the Solman study above. In this study, they avoided that mistake and found that the risk of heart failure admission was higher on refecoxib and non-selective NSAIDs vs celecoxib (number needed to harm 14, 14, 24, respectively). Also, patients with no history of cardiovascular medication use were more likely to end up on them in the NSAID users. These are important findings given that 28% of Ontario seniors were prescribed these medications.

We have known for many years that non-selective NSAIDs may exacerbate heart failure by causing salt and water retention, but this study suggests that heart failure may even by precipitated for the first time with these drugs, especially rofecoxib. They suggest that rofecoxib may be more risky because of its long half-life and tendency to accumulate in the body, but believe caution is advised with all NSAIDs in patients at risk for heart failure. Also, their data are consistent with other studies showing that rofecoxib increases blood pressure more than other NSAIDs. This may contribute to heart failure initiation or decompensation.

This retrospective observational study suffers from the problem of bias due to unrecognized confounders. Also, this study had recognized confounders in that the coxib users were likely to have a higher incidence of pre-existing cardiovascular disease. In addition, no dosage data were available, but interestingly, < 10% of subject on rofecoxib were on < 25 mg/day. In summary, it would appear that the use of coxib drugs should be used with caution in patients at high risk for ischemic heart disease events or heart failure. Rofecoxib doses > 25 mg/day in particular should be avoided in such patients.

Dr. Crawford is Professor of Medicine, Associate Chief of Cardiology for Clinical Programs, University of California, San Francisco.